6-amino-5h-dibenzo[d, f][1, 3]diazepines



The present invention is concerned with a group of 6-amino-5H-dibenzo[d,f][l,3]diaz epines having the following formula, the acid addition salts of these substances,

and with processes for their preparation. As maid in dealing with nomenclature questions, the positions of the ring structure are numbered according to the system used by Chemical Abstracts.

Formula I In Formula I the symbols A and B refer to one or two substituents attached respectively at the 1, 2, 3, 4, or 8, 9, 10, 11 positions of the phenyl rings indicated. These substituents are selected'from hydrogen, fluorine, chlorine, bromine, iodine, trifiuoroinethyl, and alkoxy, alkyl,

United States, Patent 0 and carbalkoxy, each having up to seven carbon atoms. 7

The symbol E refers to an amino or substituted amino group attached at the 6-position.

Amino groups contemplated by the symbol E in Formula I include-NHOH, morpholino, thiamorpholino, piperidino, pyrrolidino, hexamethyleneimino, 4-(lower alkyl)piperazino, wherein the lower alkyl group contains up to four carbon atoms,

1 and N Alk-Y bol Alk is an alkylene group having up to three carbon atoms, and Y is an amino group selected from morpholino, thiamorpholino, piperidino, pyrrolidino, 4-(1ower aIkyDpiperazino, wherein the lower alkyl group contains up to four carbon atoms, and amino ofthe formula wherein R has the same meaning as above.

These substances and the salts thereof with pharma- "ice phoric acid, nitric acid, citric acid, succinic acid, gluconic acid, the alkyl, aryl, and aralkyl sulionic and sulfuric acids having up to 20 carbon atoms such as methanesulfonic acid, p-toluenesulfonic acid, lauryl sulfuric acid, etc., the lower alkanoic acids such as acetic, propionic, and butyric acid, rnucic acid, and the like, which are non-toxic and do not elicit undesired physiologic effects in their own right in the doses required for administration of the substances of Formula I.

The compounds and the salts thereof with pharmaceutically acceptable acids variously possess antifu-ngal, antibacterial, anticonvulsant, muscle relaxant, interneuronal depressant, and a variety of psychotropic effects. The psychotropic effects elicited thereby on administration to animals are characterized as stimulant, a ggressant, tranquilizing, and sedative. Their antifugal and antibacterial activity is manifested by the capacity of various members of the series to inhibit the growth of the following microorganisms in vitro:

Trichophyton menragrophytes (gypseum) ATCC 9129 T richophyton mentagrophytes (interdigitale) ATCC 9972 M icrosporium audom'ni ATCC 9079 B. subtilis K. pneumoniae M. am'eus S. pyogenes E. Coli Proteus morganii S. typhomureum S. fecali s The substances of Formula I and their pharmaceutically acceptable acid addition salts are exceedingly potent in their effect on the central nervous system when'administered either orally or parenterally to animals in dosages of from 0.1 to mg./kg. of body weight. Measurement of acute toxicities of these compounds in animals indicates that a wide margin of safety exists between the lethal dose and the effective dose'thereof. The durations of action of the various specific substances of Formula I vary considerably, some being very short acting and other exhibiting prolonged effect.

Salts of the compounds of the present invention with pharmaceutically unacceptable acids are also contemplated as part of the present invention, since they are sometimes useful as chemical intermediates in the prep-' aration of either the G-aminodibenzodiazepines themselves ceut-ically acceptable acids are biologically active and have pharmaceutical uses. Reference to salts of pharma-.

ceutically acceptable acids is meant to refer to the salts of these compounds with acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosor their pharmaceutically acceptable acid addition salts. Such acids include those which are not physiologically tolerable for seasons of toxicity, irritation, or sensitization, or because of pharmaceutical inelegance. In this category the tollowingm-ay be mentioned: perchloric acid, arsenous and arsenic acids, acids such as D-camphorsulfonic acid which may be useful in resolving optically active members of the class, and others which'may be desirable for synthetic purposes when the salts thereof possess desirable chemical or physical properties, but which are physiologically intolerable.

Three related processes are employed for the prep aration of the products of the present invention. Method A involves reaction of ammonia or an ammonium salt, hydroxylamine or a hydroxylamine acid addition salt, a primary amine or a secondary amine, or acid addition salts thereof with a G-alkylthio or 6-benzylthio reactant of Formula H or an acid addition salt thereof. This process is representedby the following equation in which is RSH refers to by-product mercaptan corresponding to the SR group of Formula II.

METHOD A SR.-l-Amine Formula I+RSH N Formula II The intermediates of Formula II are the subject of our copending application SerialNo. 229,196, filed October 8, 1962. This application is a continuation-inpart of application Serial No. 229,195, which was filed therewith.

The symbol R in Formula II refers to the benzyl group or. to -a. lower alkyl group having up to four carbon atoms. A and B have the same'meanings as above. These intermediates are prepared from. -mercapto-SH- dibenzo[d, f][1,3]diazepine or analogs thereof, having the appropriate substituents, A and B in the phenyl rings thereof by reaction with a lower alkyl chloride, bromide, or iodide. The preparation of 6-meroapto-5H- dibenzo[d,f][1,3]diazepine by reaction of carbon disulfide with 2,2-diaminobiphenyl has been described in the literature (Le Fevre, J. Chem. Soc. 733 (1929)). The analogs thereof wherein'A and B are other than hydrogen are prepared in a similar fashion.

Method B employs a 2,2'-diaminobiphenyl of the type used in the preparation of the intermediates of Formula II directlyin the preparation of the compounds of. Formula I. This method involves the reaction of a dialkyl carbodiimide or a dicycloalkylcarbodiimide with theap propriate 2,2'-diarninobiphenyl. In-some instances this method is'more convenient and offers operating advantagcs. over that of Method A. It is represented by the following equation in which R is an alkyl or cycloalkyl group havingvup to seven carbon atoms.

NHR R NHz Method C is particularly adapted for the. preparation METHOD 0 -Nn, Nn,. NH I RS-C -NH2 asn NH, NH-HX N EX These processes are discussed in more detail in the following paragraphs and illustrations for the methods by means .of specific examples are given.

METHOD A the-reaction to take place at an appreciable rate. The

upper temperature limit is governed by the thermal stability of the products and reactants. A .reactlon temperature of 200 C. has been found convenient in a num-.

ber of instances.

In some instances where a liquid amine serves as the amine reactant, an excess of the amine is employed as solvent, but ordinarily no solvent is used. In those in stances where both reactants are solids, theyare simply mixed and heated'until reaction occurs. I

It is preferred toremploy an acid addition salt of either the diazepine or the amine reactant with a mineral acid or organic sulfonic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, benzenesulfonic, or toluenes-ulfonic acid. Generally reaction occurs at a lower temperature when employing an acid addition salt as one of the reactants in the process than when reaction is effected between the free base forms of both amine and diazepine reactants.

Preparations 1, 2, and 3 below describe the preparation of G-methylthio-SH-dibenzo[d,f][1,3]diazepine, its

hydrochloride salt, and its hydroiodide salt which have proven to be convenient starting materialsfor this method. Examples. 1, 2, and 3 illustrates the use of these three starting materials under various reaction conditions for the preparation of 6-amino-5H-dibenzo[d,f][-1,3]diazepines of the present invention. Table I contains a summary of directions for the preparationof a number of additional compounds of the present invention. The physical properties of these and other compounds described herein are listed in Table III.

Preparation 1: 6methylthio-5H-dibenzo[dj] [J,3]di azepine. hydroiodide.6-mercapto-5H-d:ibenzo [d,f] [1,3]:

diazepine (Le Fevre, J. Chem. Soc. 733 (1929)); 31.5 g.

'(0.14 mole), is dissolved in 260 ml. of tetrahydrofuran and stirred for 2 hours with 21 g. (0.15 mole) of methyl iodide. After the mixture has been allowed to stand overnight, the solid is collected and air dried to give 41 g. .of'white powder, M.P. 233-234 C. (dec.). This material is recrystallized from butanone methanol, yielding the purified intermediate, M.P. 233-235 C. (dec.), which exhibits infra red absorption maxima (0.5%) in KBI) at 3.2,,33, 6.1, 6.3,'6'.8, 7.0, and 13.1,u.

Preparation 2. 6-methylthi0-5H-dibenz0[dj] [1,3]diazepine, free. base form..A sample of the hydroiodide salt prepared from 45 g. of 2,2' -diaminobiphenyl as described in Preparation 1 is thoroughly mixed with 700 ml. of chloroform and 800 ml; of 5% potassium hydroxide solution. The chloroform'layer .is then sepa rated and the solvent'distilled therefrom. The residue obtained is twicerecrystallized from a mixture of chloroform and heptane to yield th purified .free base, M.P. ,165166 C. which exhibits absorption maxima in the infra red (0.5% in KBr) at 3.2, 6.1, 6.3, 6.7, 7.0, and 132 and in the ultra violet (0.01% in acetonitrile) A max. 285, and 250 mu; E 4600, and 42,700. Preparation 3: 6-methylthio -5H-dibenz0[al.f] [],3]di azepine hydrochloride.-The free base form of the desired product, prepared as described in Preparation 2 is dissolved in 500 ml. of tetrahydrofuran and acidified with dry hydrogen chloride dissolved in ethanol. The slurry is allowed to stand overnight and the white precipitate collected on a filter. It is air dried, yielding the hydrochloride salt, Ml. 223224 C. (dec.), which is employed as such without further purification in the preparation of various 6-amino-5H-dibenzo[d,f] [1',3]diazepines of the present invention.

Example l.6-dielhylctminoethylmethylamino-SH- V dibenz[d,f] [1,31diazepine A mixture of 3 g. (0.0125 mole) of 6-methylthio-5H- dibenzo[d,f] [1,31diazepine (Preparation 2) and 2 g. (0.0154 mole) of N,N-diethyl-N'-methylethylenediamine is heated and the temperature permitted to rise to 200 C, About 3 hrs. elapses in the course of this heating step, and the odor of mercaptan nearly disappears at the end. The cooled mixture is thoroughly mixed with 30 ml. of water and the liquid decanted. The gum is washed with 50 ml. of methanol, and the solvent removed by distillation to remove mercaptan odor. The product is then converted to the dihydrochloride by treatment with 5 N HCl in ethanol, and twice recrystallized from ethanol-isopropyl ether, yielding 4 g. (81%) of purified product as fine white needles, M.P. 249-250 C. (else). The analytical results for this substance are listed in Table III. Example 2.6-piperidin0-5H-dibenz0 [dj] [1,3]diazepine -methylthio-SH-dibenzo [d,f] 1,3]diazepir1e dide, 10 g. (0.027 mole, Preparation 1) is heated on a steam bath with 12 g. (0.14 mole) of piperidine for 8 hrs. The odor of methyl mercaptan becomes evident immediately upon mixing the reactants and persists throughout the heating period. Alkaline 50% ethanol is added to dissolve precipitated salts and then the mixture is diluted to 200 ml. with water. The precipitated product is collected and dried; yield, 6.5 g. (87%), colorless prisms, M.P. 142-143 C. Recrystallization from heptane yields the crystalline product as clusters of needles, Its physical properties are listed in Table Ill.

Example 3.6-(2-m0rph0lin0ethyl)amino-SH-dibenzo- [dj] [1 ,3]diazepine dihydrochloride 6 methylthio SH-dibenzo [d,f] [1,3]diazepine hydrochloride, 5.5 g. (0.02 mole, Preparation 3) is mixed with 10 g. of 4-(2-aminoethyl)morpholine and heated in an oil bath at 70-75 C. for 2 hrs. The amount of N-(2- aminoethyDmorpholine employed is in excess of the stoichiornetric quantity and serves as solvent. Evolution of methyl mercaptan is evident when the internal temperature of the reaction mixture reaches 50-65 C. At the conclusion of the heating period the reaction mixture is cooled and mixed with 250 ml. of 5% aqueous isopropa- 1101. It is chilled, the solvent decanted, and the residue dried bydistilling 3 consecutive ml. portions of absolute ethanol therefrom. The residue is then treated with an excess of 5 N ethanolic hydrogen chloride. The dihydrochloride salt of the desired product is then precipitated from the solution by treatment with diisopropyl 3 ether. The slurry is chilled, the bulk of the solvent decanted, and the gummy precipitate recrystallized from a mixture of isopropanol and methanol, yielding 4.0 g. of gray crystalline solid, M.P. 279280 C. (dec.). A second group of this product Weighing 2.0 g. is obtained by concentration of the filtrates. These samples are combined and recrystallized from aqueous methanol, yield 5.5 g. of the purified product as colorless prisms, M.P. 279-280 C. (dec.). The physical properties of this material are listed Qable'lll.

hydroio- METHOD B This method is applicable to the preparation of these compounds of Formula I in which the group E is a secondary amino group, that is it is applicable to the preparation of fi-secondary amino-5H-dibenzo[d,f] [1,31diazspines. The method involves reaction of a 2,2'-diaminobiphenyl with an alkyl or cycloalkylcarbodiimide. Alkyl and cycloalkylcarbodiimide reactants are employed in which each of the alkyl or cycloalkyl groups contains 10m one to seven carbon atoms. The method involves heating 2,2-diaminobiphenyl or a phenyl ring substituted derivative thereof with the carbodiimide reactant. The latter reactants have the formula R N==O NR in which R refers to an alkyl or cycloalkyl group having up to 7 carbon atoms. The reactants are simply mixed and heated. In this process the by-product is a primary amine, the presence of which can ordinarily be detected by odor. The process is preferably conducted at a temperature in the range -200" C. Higher temperatures. up to the decomposition temperature of either product or reactants may be employed, as may somewhat lower temperatures it longer reaction times are allowed. The product is recovered simply by allowing the reaction mixture to cool and then recrystallizing from an appropriate solvent. The following examples illustrate this method.

Example 4 .6-is0pr0pylamina-SH-dibenzo[dj] [1,3]

, diazepine Example 5.6-cyclohexylamino-SH-dibenzo [if] [1,3]diazepine The procedure of Example 4 is repeated, substituting N,N'-dicyclohexylcarbodiimide for the carbodiimide reactant specified in Example 4. The desired product is recovered in the fashion indicated in Example 4, and purified as described in that example. The properties of this substance are reported in Table III.

Example 6 6 -is0propy lamin0-3,9-dimethy [-5 H -dibenz0 [if] l fil zepine T he method of Example 4 is repeated, substituting as diarninobiphenyl starting material 2,2'-diamino-4,4'-dimethylbiphenyl, which is prepared by catalytic hydrogenation of 2,2'-dinitro-4,4-dimethylbiphenyl (P. E. Fanta, Chem. Reviews 38, 139 (1946)) over 5% platinum-oncarbon catalyst. The product is recrystallized from isopropanol-acetone mixture, yielding the desired product, M.P. 239-240 C. The physical properties of this prodnet are reported in Table III.

METHOD C This method is restricted to the preparation of those 5H-dibenzo[d,f] [1,31diazepines having a primary amino group in the 6-position. It involves reacting 2,2'-diaminobiphenyl or an analog thereof bearing one or more phenyl ring-substituents with an S-lower alkyl or benzyl pseudothiourea salt. The halide and sulfate salts are most readily available and are quite satisfactory. Again from the standpoint of availability the S-methyl compounds are preferred, methyl pseudothiourea sulfate being employed as reactant in Example 7 which is generally illustrative of themethod. The S-ethyl, S-propyl, and S-benzyl pseudothiourea salts are also operable.

As before, the process is carried out without solvent Example 7.6-amino-5H-dibenz0[dj] [1,31diazepine 2,2-diaminobipheny1, 6 g. (0.033 mole) is heated with 6 g. of S-methylpseudothiourea sulfate to 100 C., whereupon methyl mercaptan evolved. The temperature is gradually raised to 200 C. and held there for 30 minutes. The mixture forms a gum which is cooled, collected, and triturated With excess alkaline (NaOH) 30% methanol. The mixture is then diluted with 200 ml. of water, leaving the product as an insoluble tan solid, which is collected.

'It is recrystallized from 35% ethanol, yielding the purified product as pale tan flakes weighing 2.5 g.'(36%), M.P. 211 C. (dec.). The product-appears to be subject I to decomposition during the recrystallization step. The infra red spectrum and nitrogen analyses is listed in Table III.

For convenience in preparing compounds of this invention bearing phenyl ring-attached substituents, there arelisted in Table II a number of substituted 2,2-dinitrobiphenyls which have been described in the literature. Literature references for the preparation of these dinitrobiphenyls are listed by P. E. Fanta in Chem. Reviews 38, 139 (1946). Thesernaterials are transformed to corresponding 2,2-diaminobiphenyls by catalytic hydrogenation of the nitro groups or by chemical reduction thereof.

Chemical reduction-is preferred when functional groups are present in the molecule which are considered likely to interfere with or be adversely afiected by catalytic hydrogenation. An applicable chemical reduction method 0 3 isdescribed by Hodgson and P. F. Holtfin J. Chem. Soc.. 37 (1937) for the preparation of 2,2-di amino-4,4'-.dimethoxybiphenyl from 2,2 dinitro 4,4 dimethoxybh phenyl. The dinitro compound is refluxed in aqueous acetic acid with iron powder and the desired ,diamino compound is recovered by extraction with anorganic solvent such asv benzene and recovered by precipitation as the dihydrochloride salt. V

The substituted-2,2'-diaminobiphenyls are transformed to correspondinglyv substituted 6-amino-5H-dibenzo[d,f] [1,3]diazepines, according to Methods A, B, and C described above. Compounds' of Formula I :preparable from the diaminobiphenylsslisted in;Table II are also listed in that table. I

Examples 8 to 24 vents employed for recrystallization, and the substituents in the 6 position of the several end products. 7

Other phenyl ring-substituted 2,2-dinitrobiphenyls useful as starting materials for the preparation of compounds or" the present invention may be prepared by replacement of phenylring attached, amino groups of aminosubstituted-Z,2-dinitrobipheny1s. This is accomplished by diazotization of the aromatic amino groups in the usual fashion followed by' replacement of the diazonium groups as is known in the art, for instanceaccordingto the Sandrneyer or Schiemann methods. To'illustrate, benzidine is readily converted'to 2,2'-dinitrobenzidine by nitration according to the method described in Ber. 23; 794-798 (1890 The 2,2'-dinitrobenzidine is then tetrazotized as described by H. H. Hodgson, et al., J. Chem. Soc. 1620 (1937). On mixing the solution of thetetrazoniurn salt with a solution of cupous iodide in hydroiodic acid, 2,2-dinitro-4,4'-diiodobiphenyl is produced. This material is then reduced to the 2,2'-diamino compound and converted to a 6amino-5H-dibenzo[d,f][1,3]diaze pine as described herein.

TABLE I.EXAMPLES 8-24 [Preparation of 6-amin0-5Hdibenzo[d,i] [1,31diazepines1] Amine Ro'actant' A. Hydrochloride B. Hydroiodide 0. Free Base Reactants Exgrrgple Reaction temp, time Recryst. Solvent Product (Formula I,

8 B Hexamethyleneimine I. 100 0., 8 hrs Aqueous ethanol NC 9 B 4-methylpiperazine 100 0., 8hrs Methanol NON OH -2 H01 CH3 10 O (Z-dirnethylaminoethyl) methyl- 200 0., 3 hrs Methanol-isopropyl ether N amine.

' CHHzN(CHs)z 2 0H1 11 0 (2-dicthylamino-ethyDethyl- 200 0., 3hrs Ethanol-isopropanol N amino. OH2OH2N (02119221101 12 0 Dimethylamine hydrochloride 160200 0., -min ethanol N( 1 13 o Dicthylamine,hydrochloridelnnr 0., 2 4 hrs Methanol c,H, ,.no 14 0 Methylamine hydrochloride 200 0., 30 mins Hcptaneg.

. TABLE I.EXAMPLES 8-24-Continued Reactants ExIaImple Reaction temp., time Recryst. Solvent Product (Formula I, E=)

15 Ethylamine hydrochloride 170200 0., 30 mins 95% ethanol NH0 H 16 A Morpholine hydrochloride 100 0., 4hrs Methanol-isopropyl ether N O-HCI 17 A Pyrrolidine 100 0., hrs Dimcthyl-formamide-water N H01 18 A 2-aminothiazole 100 0., mins Dimcthyl-lormamitic-water; N

19 0 n-Butylarninc hydrochloride 200 0., 30 mins Methanol-diisopropyl ether --NH(CH2)3OH3-H0l 20 A Aniline 180-185" 0., 2 hrs Mcthoxy-ethanol-water -N 21 A Thiamcrpholine hydrochloride.-- 100 0., 8 hrs g .1301

22 A Z-diethylamino-ethylamine 75-80 0., 3 hrs 95% ethanol ethyl acetate -NHCH OH N(0 E .2 H01 23 A 2-dimethylamino-cthylaminc 70125 0., 3 hrs 95% ethanol-ethyl acetate NH0H CH N(0H -2 H01 24 2-morpholin0ethylamine 70125 0., 4 hrs 95% ethanol -NHCH2CH2N 0 TABLE II.PHENYL RING-SUBSTITUTED PRODUCTS OF FORMULA I NH NH Methods A, B, or 0 E Substitnted-2,2-Dinitrobiphenyl Substituted-(Semino- 5l-I-d ibenzo[d,f][l,3]

. diazepine A B Snbstituents 4-flnoro 4-fiuoro 3,9-difluoro.

lo 3,9-dichloro.

1.4,8,11-tctracl1loro.

3,9-dibron1o.

- 4,8-din1ethyl.

1,11-dirnethyl. 4-rnethyl 4-methyl 3,9-dimethyl. i-methyl-fiflchloro 4mctl1yl-6-chloro- 1,11-dichloro-3,9-

dimethyl. 4-mcthyl-6-bromo 4-n1ethyl-6-bromo 1,11-dilororno-3,9-

dimethyl. 4,6-dimethyl 4',6-dimethyl l,3,9,11-tetramethyl. 6-methoxy 6-methoxy 1,1l-dimcthoxy. 4-rnethoxy 4-methoxy 3,9-dimetl1oxy. 4-ethoxy 4-ethoxy 3,9-diethoxy. 4,5-dimethoxy- 4,5-dimethoxy 2,3,9Jdtetramethoxy. G-carborncthoxy- 6-carbomethox 1,11-dicarbornethoxy. G-carbethoxy... 6-carbethoxy LH-dicarbcthoxy.

4,8-dicarhethoxy. 3,9-dicarbcthoxy. l-carbomethoxy. 3,9-bis(triiluoromethyl) 1 Prepared by the Ullmann condensation of Q-nitrol-triiiuoromethylchlorobenzene according to the general method described by I. E. Fania, 75

0c. cit.

ydr ochloridc used as starting material.

Example 25.(a) 6-carb0xymethylamin0- H-dibenzo- [1,31diazepine tS-methylthio 5H dioenzo[d,f] [1,31diazepine hydrochloride, 5.5 g. (0.02 mole), is mixed with a solution of 1.5 g. (0.02 mole) of glycine and 0.8 g. (0.02 mole) of sodium hydroxide in ml. of Water and 20 ml. of dioxane, and the mixture is warmed on the steam bath at 50 C. for 20 hrs. The solution is then allowed to cool to room temperature to permit crystallization of the product. The product separates as a White precipitate and is recovered by filtration and dried in the air. It is then recrystallized from acetone, yielding the desired material, MP. 289290 C.

(b) 6-carbethoxymethylamino-5H dibenzo [dj] [1,3]- diazepine hydrochloride Example 26.-6-hydr0xylaminc-SH-dibenzo [dj] [1,3 diazepine hydrochloride A mixture of 4.2 g. (0.06 mole)'of hydroxylamine hydrochloride, 8.3 g. (0.03 mole) of 6-rnethylthio-5H- dibenzo[d,f][1,3]diazepine hydrochloride, ml. of dioxane, and 3.6 g. of sodium hydroxide dissolved in 50 ml. of water is prepared. The odor of methylrnercaptan is immediately apparent on mixing. The mixture is stirred at room temperature (30 C.) for 18 hrs, diluted to 200 ml. With Water, and the White precipitate collected. The white precipitate makes its first appearance after about 2 hrs. of stirring at room temperature. It is dried in the air, yielding a pure White powder, MP. 169-170 C. (dec.). This product is twice recrystallized from ethanol, yielding 7.5 g. (95%). of the desired product in purified form as colorless needles, MP. 225-226 C. (decn). The physical constants for this substance are listed in Table III.

While several particular embodiments of this invention ere ShQW1'l above, it will be understood, of course, that fore, by the appended claims, to cover any such modifi t e invention is 11011 be limited theret0, $i110e y cations as fall within the true spirit and scope of this modifications may be made, and it is contemplated, thereinv ti I TABLE Ills-PHYSICAL PROPERTIES 6-SUBSTITUTED-5H-DIBENZO [0,1] [1,3] DIAZEPINES Ultra Violet Ab Infra Red Example Analysis. sorption 1 (m Absorption 2 Melting No. G-Substituent Salt Formula (Percent by A max. (,1) Point C.)

, wt.) mam/E max.

1 (Z-diethylamino-ethyl) Dihydrochloride CzoHzgClgN, N, 13.91; 3.4, 5.1, 246-247 mothylamino. C 17.76 6.4, 6.7;, (dec.)

7.0, 13.0. 2 Piperidino Free base O1BH19N3 C, 77.76, 280 4, 850 3.0, 3.4, 144-145 H, 7.13, 243 43, 100 3.5, 6.1, N, 15.03 6.3, 6.8, 1 7 0, 13.1, 3 (Zamorpholinoethyl) Dihydrochlorlde C10Hz4N OC1z'. N, 13.90, 280 3, 160 3.1, 3.4, 277-278 amino. 7 C1, 17.05 237 48,800 6.0, 6.3, (000.)

220 32, 600 6.8, 7.0, 13.1, 13.7. 4 Isopropylamme- Free base GmHnNa C, 76.38, 275 4, 540 3.0, 3.3, 228-22p 1 5 Cyelohexylamino do CH21N3 C, 78.00, 275 3, 880 3.0, 3.4, 231-232 H, 7.37, 240 38, 300 3.5, 6.0, N, 14. 216 30, 000 6.3, 6.7, 6.8, 7.0, 13.1. 6 do-. OlsI ZlNR N, 14.80 280 4, 300. 3.0, 3.5, 244. 5240 12. 7 Amino 0 OmHuNa N, 19 90 278 3, 030 3.0, 3.3, 208-209 240 34, 900 6.0, 6.3, (1.190.)

8 Hexamethyleneimino Ethanol complex C21Hb7NaO O, 74 97, 280 4, 820 3.0, 3.4, 69-80 H, S 11, 241 41, 800 6.1, 6.3, ((100.)

N, 12 53 217 30, 700 (15.8. 7.1%. 3.1, 9 4-methylpiperazino Dihydrochloride C1 HmOl2N N, 15.11, 270 3, 650 3.4, 3.7, 310

220 r 27, 800 7.0, 13.0. 10 (Z-dimethylaminoethyl) --d0 O18II11Ol2N4 N, 14.92, 280 3, 300 3.4, 5.1, 250-251 methylamino. Cl, 19.39 240 49, 000 6.4, 6.7,

h r r 220 26,600 7.0.13. 11 (zdiethylammoethyl) 1o C21H5oC12N4 N, 13.41, 230 3, 300 3.4, 6.1, 159-161 ethylamino. C 17.11 240 43, 000 6.4, 6.7,

220 25, 900 7.0, 13. 12 Dimethylamino Hydrochloride. CH111C1N3 O, 65.97, 280 3, 070 3.3, 3.4, 310

' H, 6.13, 238 46, 400 3.5, 6.0, N, 15.06 219 37,000 13 vDiethyhminn n C17H20C1Na N, 13.70, 280 3, 470 3.4, 6.1, 310 01, 11.87 238 51, 100 6.4, 6.6,

217 30, 900 (15.37, 7.0, I 14, Methylamino -1 Free base O14H13N3 C, 75.31, 280 3, 800 3.0, 3.3, 243-245 13. 15 Ethylamino .d0 C15H15N3 O, 75.92, 280 3, 910 3.0, 3.3, 213-215 V H, 6 66, 241 40, 000 6.0, 6.3, N, 17 56 216 32, 000 (11386 7.0, 16 Morpholino. Hydrochloride C17H13N3OC1 C, 64.89, 275 3, 750 3.3, 3.5, 310

11,596, 240 57, 000 6.1, 6.4, N, 13.37, 219 28, 200 6.6, 6.7, C 11.29 1 7.0, 13.1. .17 Pyrrolidino "do CnHmNaOl, N, 13.79, 280 3, 600 3.2, 3.3, 310

219 31, 600 6.3, 6.5, 637, 7.0, .0. 18 Z-thiazolylamino Free base 01611121219. N, 19.17 312 26, 900 3.3, 3.4, 204405 S, 10.97 235 29, 200 6.0, 6.4, 638,2 7.0, 19 n-Butylamino Hydrochloride CnHzoNaCl N, 13.74, 280 3, 290 3.1, 3.2, 239-241 6.66, 6.7, 7.0, 13.1, 20 Anilino Free base CmHlsNs O, 80.05, 232; 33,800 3.0, 3.3, 255-256 H, 5.60, 3.5, 6.0, N, 14.93, 637, 22 2-diethylaminoethyl- Dihydroehloride C1aHmN C1z C, 59.18, 3.4, 60, 222. 5-222 amino. H, 7.24, 6. 7.0, N, 14.41, 13 O 18.46 23 2-dimethylaminoethyldo C17H22N4C12 C, 57.80,, 3.4, 6.0, 219221 amino. H, 6.58, 6.7, 7.0,

24 Free base C10H2uN4G1z O, 58.18, 3.4, 6.0, 215. 5-217. 5 H, 5.40, 6.3,68,

N, 14.17, 12.4. C 18.16 Garbethoxymethylaminou Hydrochloride C 7H gNaOzC1 N, 12.70, 270. 3, 300 3.3, 5.7, 193-194 C 10.60, 235 48, 6.0, 6. (090.)

See footriotes at end of table. 5 1- TABLE III.--PHYSICAL PROPERTIES 6-SUBSTITUTED-5H-DIBENZO [d,f] [1,3] DIAZEPINES-Continued Ultra Violet Ab- Infra Red Example Analysis sorption 1 (my) Absorption 2 Melting No. G-Substituent Salt Formula (Percent by max. (,1) Point C.)

' wt.) maxJE max.

26 Hydroxylamino Hydrochloride ClflHlflNiClO- C, 59.57, 295 3, 430 3.3, 6.0, 225-226 H, 4.93, 235 38, 200 6.4, 6.7, (dec.) N, 16.00, 7.0, 13.1. Cl, 13.79

1 At a concentration of 0.01 mg./ml. in 95% ethanol. 2 At a concentration of 0.5% in crystalline KBr. B G-isopropylamino-3,9-dimethyl-H-dlbenzo[d,f1[1,31d1azepme.

4 G-(Z-morpholinoethylamino)-3,9-dichloro-5H-dibenzo[d,t][1,31diazepine.

What is claimed is: 1. A compound selected from the group consisting of a compound of the formula and the acid addition salts hereof ,wherein A'and B each represent up to two phenyl ring-attached substituents selected from the group consisting'of hydrogen, fluorine, chlorine, bromine, iodine, trifiuoromethyl, and alkoxy, alkyl, and carbalkoxy each having up to seven carbon atoms, and wherein E is an amino group selected from the group consisting of hydroxylamino, morpholino, thiamorpholino, piperidino, pyrrolidino, hexamethyleneimino, 4-(lower alkyl)piperazino in which the lower alkyl group has up to four carbon atoms,

wherein R is selected from the group consisting of hydrogen, alkyl, and cycloalkyl each having up to seven carbon atoms, R is selected from the group consisting of alkyl, carboxyalkyl, carbalkoxyalkyl, cycloalkyl each having up to seven carbon atoms, hydrogen, phenyl, and thiazolyl, Alk is an alkylene group having up to 3 carbon atoms, and Y is an amino group selected from the group consisting of morpholino, thiomorpholino, piperidino, pyrrolidino, 4-(lower alkyl)-piperazino, in which the lower alkyl group has up to four carbon atoms, and amino of the formula wherein R has the same meaning as above.

2. The compound of claim 1 wherein A and B are hydrogen and E is alkylamino.

3. The compound of claim 1 wherein A and B are hydrogen and E is dialkylamino.

4. 6-isopropylarnino-5H-dibenzo [d,f] 1,3]diazepine.

5 6-piperidino-5H-dibenzo [d,f] [1,3 di azepine.

6. 6 hexamethyleneimino 5H dibenzo[d,f] [1,3]- diazepine.

7. 6-diethylamino-5H-dibenzo[d,f] 1,3] diazepine.

8. 6-pyrrolidino-5H-dibenzo [d,f] [1,3 1 diazepine.

9. The process which comprises heating a 2,2'-diarninodiphenyl reactant of the formula wherein A, B, and R have the same meaning as above.

10. The process which comprises heating a compound selected from the group consisting of the S-benzylpseudothiourea sulfates and halides, and S-lower alkylpseudothiourea sulfates and halides having up to 4 carbon atoms in said lower alkyl group with a 2,2-diarninodiphenyl reactant of the formula wherein A and B each represent up to two phenyl ringattachcd substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, alkoxy, alkyl, and carbalkoxy having up to seven carbon atoms,

l5 15 at a temperature of at least about 110 C. thereby producwherein A and B have the same meaning as ab'ove. ing a compound of the formula 11. The process of claim 10 wherein methyl pseudo- A thiourea sulfate is employed.

5 References Cited in the file of this patent UNITED STATES PATENTS 3,098,075 Druey et a1 July 16, 1963 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 9. THE PROCESS WHICH COMPRISES HEATING A 2,2''-DIMAINODIPHENYL REACTANT OF THE FORMULA
 10. THE PROCESS WHICH COMPRISES HEATING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE S-BENZYLPSEUDOTHIOUREA SULFATES AND HALIDES, AND S-LOWER ALKYLPSEUDOTHIOUREA SULFATES AND HALIDES HAVING UP TO 4 CARBON ATOMS IN SAID LOWER ALKYL GROUP WITH A 2,2''-DIAMINODIPHENYL REACTANT OF THE FORMULA 